A new synthetic approach to phenothiazine-2-amines

Article abstract of DOI:10.1016/j.tetlet.2012.07.083

Elaboration of a Buchwald-Hartwig protocol for the introduction of amino functions to position 2 of the phenothiazine ring system has opened a new access to various N-alkyl and N-dienyl phenothiazines bearing secondary amines, tertiary amines, and amide moieties. Hydrolysis of the amido derivatives gave unsubstituted phenothiazine-2-amines. This protocol provides an easy access to phenothiazine-2-amines starting from the commercially available starting compounds.

Full text of DOI:10.1016/j.tetlet.2012.07.083

Tetrahedron Letters 53 (2012) 5585–5588
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Tetrahedron Letters
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A new synthetic approach to phenothiazine-2-amines
⇑
Daniella Takács, Orsolya Egyed, László Drahos, Zsuzsanna Riedl, György Hajós
Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Pusztaszeri út 59-67, H-1025 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Elaboration of a Buchwald–Hartwig protocol for the introduction of amino functions to position 2 of the
phenothiazine ring system has opened a new access to various N-alkyl and N-dienyl phenothiazines bear-
ing secondary amines, tertiary amines, and amide moieties. Hydrolysis of the amido derivatives gave
unsubstituted phenothiazine-2-amines. This protocol provides an easy access to phenothiazine-2-amines
starting from the commercially available starting compounds.
Received 5 April 2012
Revised 29 June 2012
Accepted 19 July 2012
Available online 27 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Phenothiazine
Amination
Buchwald–Hartwig cross-coupling
Functionalization
Fairly extensive research on phenothiazine derivatives has ap-
peared in the literature due to the valuable biological properties
of such compounds.1 Thus, inhibitors of multidrug resistance,2
inhibitors of mitotic kinesin Eg5 and trigger apoptosis,3 potential
antimicrobial agents,4–6 antitumor agents,7 antitubercular com-
pounds,8 potential chemotherapeutic agents,9 and antioxidants10
have been reported.
HNR1R2 (1.2 equiv.)
Pd2(dba)3
S
S
N
XPhos
NaOtBu
NR1R2
N
Cl
toluene, Ar
110 °C, 24 h
Bn
5
Bn
6
Although considerably large diversity in the substituents on
these compounds has been published, relatively little information
is available for aminophenothiazines. Whereas ring-closure tech-
niques11 and more complicated procedures12 to such compounds
have been reported, no general methodology has appeared that
could provide a general approach to such amines.
In this Letter we report on a simple and general protocol for the
conversion of commercially available 2-chlorophenothiazine (1)
and related compounds into the corresponding 2-amine and 2-
amide derivatives by using the Buchwald–Hartwig cross-coupling
technique.
In order to carry out the desired cross-coupling amination, pro-
tection of the ring nitrogen atom of the thiazine moiety was
deemed appropriate. To this end, 1 was reacted with di-tert-butyl
dicarbonate to give the Boc-protected compound 2,13 which was
subjected to Buchwald–Hartwig cross-coupling14 with primary
and secondary amines and amides (Scheme 1).15 Five products
3a–e were obtained in moderate to excellent yields (Table 1).
The protecting group could be easily removed by treatment with
trifluoroacetic acid to give the unprotected products 4a–e in
acceptable yields (Table 2).
HNR1R2 = N-aminoethyl-morpholine
a
b
BnBr
HNR1R2 = morpholine
1. NaH (60%)
THF, Ar
73%
0 - 5 °C, 1 h
O
O
2. 5 -10 °C, 2 h
O
O
O
DMAP
Et3N
S
S
THF
N
Cl
0 °C RT, Ar
84%
N
H
Cl
Boc
2
1
HNR1R2
Pd-catalyst
XPhos
CF3COOH
CH2Cl2
S
S
base
Ar, 0 °C
NR1R2
RT
2
toluene
Ar, 110 °C
NR1R2
N
N
H
Boc
3
4
⇑
Corresponding author.
E-mail address: hajos.gyorgy@ttk.mta.hu (G. Hajós).
Scheme 1. Synthetic pathway to phenothiazine-2-amines. Anhydrous solvents and
Et3N were used.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.083

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D. Takács et al. / Tetrahedron Letters 53 (2012) 5585–5588
Table 1
Experimental conditions and yields for the formation of N-protected phenothiazine-2-amines (3)a
Product
Amine/ Amide
Pd-catalyst (mol %)
Base (2 equiv)
NaOtBu
Yield (%)
60
O
O
N
3a
7.5 Pd2(dba)3
NH2
3b
3c
5 Pd2(dba)3
NaOtBu
NaOtBu
88b
63
NH
N
O
NH
7.5 Pd(OAc)2
3d
3e
7.5 Pd2(dba)3
7.5 Pd2(dba)3
K2CO3
78
57
H
NH2
O
Cs2CO3
H3C
NH2
a
In each case, 15 mol % of XPhos ligand (2-dicyclohexylphosphino-20,40,60-triisopropylbiphenyl) was used.
With 10 mol % of XPhos.
b
Thirteen N-dienylamines and amides 8a–m were prepared, and
the yields and experimental conditions are summarized in Table 3.
2-Chloro-N-dienylphenothiazine compound 9 containing a bro-
mine substituent on the phenyl ring was able to react with mor-
pholine at both halogen atoms (Scheme 3). Thus, when 1.2 equiv
of amine was used, monoamination took place with the displace-
ment of the bromine atom (i.e. 10 was formed in 44% yield),
whereas with 2 equiv the dimorpholino compound 11 was ob-
tained in 70% yield.
Consideration of the above findings revealed that this protocol
could be successfully applied for the elaboration of an easy synthe-
sis of phenothiazine-2-amine hydrochloride salt, a functionalized
phenothiazine derivative which was previously only available
through fairly complicated syntheses: either by nitration of the
phenothiazine followed by reduction under harsh conditions,18 or
by a ring-closure reaction to the related carbamate involving ele-
mentary sulfur followed by hydrolysis.19,20 The key to this simpli-
fied synthesis is that phenothiazine amides 4d,e can be hydrolyzed
to the desired primary amine as reported earlier.19 In our hands,
hydrolysis of these amides was accomplished in 1,4-dioxane with
10% hydrochloric acid (4d at rt for 1 h, 4e at 100 °C for 30 min)
to give phenothiazine-2-amine hydrochloride (12) in 80% yield.
Furthermore, the N-protected formamide 3d was treated with
hydrochloric acid at room temperature for 70 min (Scheme 4). Un-
der these conditions hydrolysis of the amide function and removal
of the protecting group occurred simultaneously to afford pheno-
thiazine-2-amine hydrochloride salt (12) in an acceptable 58%
yield (Scheme 4).21 This sequence enables the synthesis of amino
compound 12 from commercially available 2-chlorophenothiazine
(1) in three simple steps.
Table 2
Yields of the deprotection reactions of 3 to give phenothiazine-2-amines and amides
4
Product
Amine/ Amide
Yield (%)
50
O
O
N
4a
NH2
NH
4b
4c
62
80
N
O
NH
4d
4e
53
58
H
NH2
O
H3C
NH2
The cross-coupling reaction was also successfully carried out in
the presence of a benzyl protecting group16 (via preparation of 5
and transformations into 6), mostly in good yields. Removal of
the benzyl protecting group, using 6b as an example, was not
straightforward and the yield was found to be low (see Supple-
mentary data).
This amination methodology was also applicable for the trans-
formation of 2-chloro-N-tetrazolyldienylphenothiazine 7, prepared
by us recently (Scheme 2).17
Thus, the chloro compound 717 was reacted with primary
amines, secondary amines, and amides under Buchwald–Hartwig
conditions resulting in the formation of the corresponding 2-amino
derivatives 8.
In summary, the above findings reveal that the palladium-
catalyzed Buchwald–Hartwig amination of 2-chlorophenothiazine
HNR1R2 (2 equiv.)
Pd-catalyst
ligand
S
N
S
N
base
NR1R2
Cl
N
toluene, Ar
110 °C, 0.5-24 h
N
N
N
N
N
N
OMe
OMe
N
7
8
Scheme 2. Synthesis of 2-amino-N-dienylphenothiazines.

D. Takács et al. / Tetrahedron Letters 53 (2012) 5585–5588
5587
Table 3
Experimental conditions and yields for the formation of N-tetrazolyldienylphenothiazine-2-amines 8a
Product
Amine/amide
Pd-catalyst (mol %)
T (°C)
Time (h)
19
Yield (%)
N
8a
7.5 Pd2(dba)3
110
56
NH2
O
N
8b
8c
7.5 Pd2(dba)3
7.5 Pd2(dba)3
110
110
1.5
1.5
65
74
NH2
NH2
CH3
NH2
8d
8e
8f
7.5 Pd2(dba)3
7.5 Pd2(dba)3
7.5 Pd2(dba)3
80
0.5
3
52b
56
H
NH
110
110
H
N
24
71
NH
8g
8h
8i
5 Pd(OAc)2
7.5 Pd(OAc)2
7.5 Pd(OAc)2
5 Pd(OAc)2
110
110
110
110
2
73c
72
O
N
O
3
NH
2.5
1.5
86
NH
NH
8j
76c
8k
8l
7.5 Pd2(dba)3
7.5 Pd2(dba)3
110 (2 h), 120 (6 h in a sealed tube)
120 (in a sealed tube)
8
65b
86d
H
NH2
O
19
H3C
NH2
O
8m
7.5 Pd2(dba)3
110 (3 h), 120 (17 h in a sealed tube)
20
45b
NH2
2 equiv of NaOtBu (unless otherwise noted) and XPhos (15 mol %) were used.
Reaction carried out with 2 equiv of K2CO3.
Reaction conducted with 10 mol % of XPhos.
a
b
c
d
Reaction carried out with 2 equiv of Cs2CO3.
S
N
Cl
N
N
N
Br
N
9
HN
O
Pd2(dba)3
XPhos
NaOtBu
toluene, Ar
110 °C, 2.5 h
S
N
S
Cl
N
N
R
N
N
N
N
N
R
N
R
N
10
R=morpholine
11
Scheme 3. Formation of mono- and dimorpholino derivatives (10 and 11, respectively) depending on the amount of reagent.

5588
D. Takács et al. / Tetrahedron Letters 53 (2012) 5585–5588
7. Motohashi, N.; Kawase, M.; Saito, S.; Sakagami, H. Curr. Drug Targets 2000, 1,
1. HCl (10%),
S
237.
RT, 70 min
2 steps
1,4-dioxane
2. HCl/Et2O
HCl
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3d
1
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N
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12
Scheme 4. Conversion of 2-chlorophenothiazine (1) into phenothiazine-2-amine
hydrochloride salt (12).
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and related compounds provides an easy and general access to
phenothiazine-2-amines and amides.
15. General procedure for the preparation of Boc-protected phenothiazine-2-
amines and 2-amides 3a–e: A round–bottomed flask was charged with Pd-
catalyst (5.0–7.5 mol %), XPhos (10–15 mol %), tert-butyl-10H-phenothiazine-
10-carboxylate (2, 1 equiv), amine/ amide (2 equiv), base (2 equiv), and dry
toluene (5 ml). The flask was flushed with argon for 5 min. The resulting
mixture was heated at reflux with magnetic stirring for 0.5–4 h. After cooling
to room temperature the mixture was concentrated and the residue purified by
flash column chromatography on silica gel using the appropriate eluent.
16. Self, J. L.; Khanapure, S. P.; Biehl, E. R. Heterocycles 1991, 32, 311.
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Geterocycl. Soedin. 1967, 3, 668.
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3697–3699, 3628–3630.
20. Richards, L. E.; Pieniaszek, H. J.; Schatzmiller, S.; Page, G. O.; Blom, K. F.; Read, J.
M.; Davidson, A. F.; Confalone, P. N. Xenobiotica 1997, 27, 217.
Acknowledgment
Financial support from the Hungarian Scientific Research Fund
OTKA-NK 77784 is gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online (detailed experimentals for all compounds including 1H
and 13C NMR spectral assignments, and elemental analysis) ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2012.07.083.
References and notes
21. To
a solution of tert-butyl-2-formamido-10H-phenothiazine-10-carboxylate
(3d, 0.1 g, 0.29 mmol) in 1,4-dioxane (2.7 ml), 10% aqueous HCl (2 ml) was
added dropwise at room temperature over 20 min. After completion of the
reaction (70 min, approximately) the mixture was poured onto ice water, made
alkaline with 10% aqueous Na2CO3 and extracted with CH2Cl2 (3 ꢀ 5 ml). The
combined organic phase was dried over anhydrous Na2SO4, filtered and
concentrated. The residue was purified by column chromatography on silica
gel (gradient CHCl3: MeOH = 10:1). The product was dissolved in Et2O, and a
few drops of MeOH then 4 N HCl/ Et2O were added at 0 °C. The product 12
(hydrochloride salt) was isolated by filtration as green-grey crystals (40 mg,
58%), mp 238–242 °C.
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